Project Summary: Neutrophilic dermatoses, characterized by neutrophil infiltrated inflamed skin, comprises of several diseases that include Sweet's syndrome, pyoderma gangrenosum, subcorneal pustular dermatosis and hidradenitis suppurativa. In a mouse model of neutrophilic dermatosis (Ptpn6spin mutant mice), we showed that IL-1R- mediated inflammatory disease is inflammasome and IL-1? independent; requires IL-1?, and is potentially driven by RIPK1. However, our current understanding of the roles and regulation of IL-1? in inflammatory disease is severely limited. Our preliminary studies show that RIPK1 and TAK1 signaling drive disease and skin inflammation in Ptpn6spin mice. Furthermore, our data suggest that microbiota may play a significant role in regulating IL-1? expression/production by the radioresistant cells that ultimately provokes disease. Thus, the overall goals of this project are to define the upstream events that regulate the mechanisms of IL-1? production in inflammatory disease. In Aim 1, we propose to examine the role of microbiota in directly regulating IL-1?-mediated skin inflammation in Ptpn6spin mice and further identify the specific cell population that are responsible for IL-1? production in the radioresistant compartment. In Aim 2, we will investigate the molecular mechanisms of SHP1-mediated disease induction in Ptpn6spin mice. In brief, we will elucidate how SHP1 regulates myelopoiesis (hallmark of disease), IL-1? induced signaling and RIPK1/TAK1 to regulate skin inflammation. The studies proposed here will break new ground in this area, and will help to uncover novel biomedical targets that function in these understudied inflammatory pathways.